Objective We aimed to assess whether differences in energy metabolism in fibroblast cell lines derived from patients with Huntington disease were associated with age at onset independent of the cytosine-adenine-guanine (CAG) repeat number in the mutant allele. Methods For this study, we selected 9 pairs of patients with Huntington disease matched for mutant CAG repeat size and sex, but with a difference of at least 10 years in age at onset, using the Leiden Huntington disease database. From skin biopsies, we isolated fibroblasts in which we (1) quantified the ATP concentration before and after a hydrogen-peroxide challenge and (2) measured mitochondrial respiration and glycolysis in real time, using the Seahorse XF Extracellular Flux Analyzer XF24. Results The ATP concentration in fibroblasts was significantly lower in patients with Huntington disease with an earlier age at onset, independent of calendar age and disease duration. Maximal respiration, spare capacity, and respiration dependent on complex II activity, and indices of mitochondrial respiration were significantly lower in patients with Huntington disease with an earlier age at onset, again independent of calendar age and disease duration. Conclusions A less efficient bioenergetics profile was found in fibroblast cells from patients with Huntington disease with an earlier age at onset independent of mutant CAG repeat size. Thus, differences in bioenergetics could explain part of the residual variation in age at onset in Huntington disease.

Additional Metadata
Persistent URL dx.doi.org/10.1212/NXG.0000000000000275, hdl.handle.net/1765/111380
Journal Neurology: Genetics
Citation
Gardiner, S.L. (Sarah L.), Milanese, C, Boogaard, M.W, Buijsen, R.A.M, Hogenboom, M. (Marye), Roos, R.A.C, … Aziz, N.A. (N. Ahmad). (2018). Bioenergetics in fibroblasts of patients with Huntington disease are associated with age at onset. Neurology: Genetics, 4(5). doi:10.1212/NXG.0000000000000275